Lung transplantation is an accepted modality of treatment for advanced stage lung disease. Since the early 1990s, more than 25,000 lung transplants have been performed at centers around the world. Patients with advanced stage pulmonary disease have multiple causes of respiratory failure including chronic obstructive pulmonary disease (COPD), restrictive lung diseases including idiopathic pulmonary fibrosis (IPD), cystic fibrosis (CF), alpha1-antitrypsin disease, primary pulmonary hypertension, and various less common causes. Patients are considered for lung transplantation when life expectancy is not predicted to exceed 24-36 months despite optimal and maximal medical management and they have class III and IV New York Heart Association (NYHA) symptoms.
However, while transplantation is an appropriate lifesaving measure for some patients, in addition to the considerable economic and social cost of lung transplantation, the long-term survival statistics for transplant recipients poses a sobering burden. The International Society for Heart and Lung Transplantation Registry reports a 1-year survival rate of 78% and 5-year survival rate of 51% following lung transplantation (Christie et al. (2008) J Heart Lung Transplant. 27:957-969). Mortality is highest in the first year, and attrition is consistent across the subsequent time periods. A major cause of transplant rejection is bronchiolitis obliterans syndrome (BOS), a lung disease characterized by fixed airway obstruction. The reported incidence of BOS is 51% by 5.6 years post-transplant, as stated in the 2008 ISHLT registry report (Lama (2009) Am. J. Respir. Crit. Care Med. 179:759-764; herein incorporated by reference in its entirety). BOS is correlated with inflammation and scarring occurring in the airways of the lung, resulting in severe shortness of breath and dry cough. Whereas patients with noncompromised lungs have FEV1 (forced expiratory volume in 1 second) values of 80% of predicted values, bronchiolitis obliterans reduces FEV1 to 16% to 21%.
Treatment options for BOS are extremely limited. Late-stage BOS is largely refractory to therapy, and thus BOS is the most common indication for re-transplantation, accounting for 52% of all re-transplantation cases (Lama (2009) Am. J. Respir. Crit. Care Med. 179:759-764; herein incorporated by reference in its entirety). Modest success has been reported for treatment of early-stage BOS with azithromycin (Lama (2009) Am. J. Respir. Crit. Care Med. 179:759-764; Gottleib et al. (2008) 85:36-41). However, there is a dearth of reliable diagnostic tests capable of detecting early-stage BOS. Better methods are needed to predict risk of BOS, occurrence of early-stage BOS, and risk or occurrence of other immunological or injury-associated causes of lung transplant rejection.